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PROSTAGLANDINS AND INDUCTION OF LABOUR
808 BREATH-SOUND CHANGES AFTER CIGARETTE SMOKING
The figure shows representative segments of polygraph tracings obtained in the women and the hamsters. The
SIR,-We describe here a system for phonographic study of breath sounds in rodents and in man which
last two segments at the bottom represent observations made in an experiment where 10 hamsters were recorded and then exposed to 8 puffs of a reference cigarette before recording the last segment in the chart. The statistical significance of the results supports the clinical impression that this simple method may be sensitive enough to detect early (acute) effects of air pollutants in human subjects. The method is also a helpful adjunct for the evaluation of experimental animals during inhalation studies. The apparatus produces permanent records of acute and chronic respiratory changes and could readily be adapted for telemetry and/or
appears to refine the performance of auscultation. This method produces permanent records for visual or computer analysis and detects, for example, early as well as chronic effects of cigarette smoking. A Grass Instrument Co. multichannel recorder model 7 was used, to which were connected E.C.G. leads (right arm/left leg), output leads of a thermocouple placed in the nares or mouth to mark inhalation and exhalation, and leads to record microphone signals taken from the chest wall. The microphone signals were also filtered and integrated to eliminate chest sounds unrelated to respiration. 205 Syrian hamsters of the BIO 87.20 and BIO 15.16 strains were subjected for up to 80 weeks to cigarette smoke from 1R1 Kentucky reference cigarettes for 8 minutes, twice a day, 5 days a week. 62 non-smoking animals were studied as controls. Variations from normal breath sounds of control hamsters were detected in most of the smoke-exposed animals by direct auscultation, and there was excellent correlation between clinical impression based on conventional auscultation and phonographic anomalies. Histopathology of the lungs was studied after pulmonary inflation and fixation under controlled pressure, and there was excellent correlation between anomalies observed microscopically and those detected by phono-
graphy. of about 25 were studied by taping the a spot in the midscapular line about 1 cm. below the shoulderblade. 1 was a chronic asthmatic, 1 a healthy non-smoker, and 1 a light-to-moderate smoker who abstained from smoking for a week before study. A control phonogram was taken of the abstaining smoker, which was identical with that of the normal subject. Immediately after inhalation of 8 puffs at 1-minute intervals from 1R1 Kentucky reference cigarettes, the wave-forms of the phonogram changed to resemble those seen in the asthmatic subject. By direct auscultation only questionable changes could be heard. 3
women
microphone
on
Phonographic recordings
of smoking and and hamsters.
non-smoking
women
personal monitoring. Bio-Research Institute, Inc., Cambridge, Massachusetts 02141, U.S.A.
C. W. LAIRD F. HOMBURGER.
Lemuel Shattuck Hospital,
Jamaica Plain, Massachusetts 02130, U.S.A.
S. ISHIKAWA.
PROSTAGLANDINS AND INDUCTION OF LABOUR
SiR,—The current preoccupation with and popularity of prostaglandin therapy in obstetrics1 is understandable since the pharmacological actions of these fatty acids make them potentially valuable therapeutic agents in a variety of conditions. We wish, however, to introduce a note of caution before these drugs are used in circumstances where they may be harmful rather than helpful. There is evidence2 that prostaglandins are more reliable and successful than oxytocin in the induction of labour before term, and in your leading article it is suggested that they may be used in the treatment of patients with, amongst other conditions, severe pre-eclampsia or cardiac disease because of the relative insensitivity of the uterus to oxytocin short of term. It would, therefore, seem
logical preferentially to use prostaglandins in those complications of pregnancy such as essential and renal hypertension, pre-eclampsia, growth-retarded fetuses, diabetes, and rhesus incompatability where induction of labour prior to term may be indicated. We think this could be false logic for the following reasons. First, there is now very good evidencë that in the hypertensive states of pregnancy pathological lesions develop in the uteroplacental arteries that almost certainly interfere with utero-placental blood-flow ; it may well be that defective maternal blood-supply to the feto-placental unit will prove to he a factor in other forms of p!acental insufficiency. Second, in pre-eclampsia there is an inadequate response of the utero-placental arteries to placentation4 resulting in their retaining more musculoelastic tissue, and hence probably being more reactive to vasomotor influences, than the corresponding placental bed arteries of normal pregnancy. Third, prostaglandm F2a has been shown to have a vasoconstrictive effect on placental veins5 and on the umbilical arteries,6 and it is thought to induce labour by causing contraction of the myometrial smooth muscle, although no studies have !cm made upon its effect on the smooth muscle of ute;’;;B blood-vessels. Consideration of these observations leads us to suspect that the exhibition of prostaglandins for the premature induction of labour in pregnancies complicated by hypertensive states, and possibly in other c(-i,ditions associated with intra-uterine hypoxia. might result in aggravation of fetal distress. The absence c: evidence of ill-effect to the fetus in prostaglandin-induced labour in normal pregnancy! is no guarantee of safet) with similar therapy in abnormal pregnancy. Before s’.ib-
809 women with abnormal pregnancies to clinical trials of induction by prostaglandins it would be wise to undertake experiments on the effect of prostaglandins on the pregnant uterus in the laboratory animal and particularly in animals where the uterus has been made ischaemic. It should not be difficult to make in-vitro studies of biopsy specimens of the human pregnant uterus, taken at the time of hysterotomy or caesarcan section, to investigate the action, if any, of prostaglandins on the myometrial blood-vessels. We think that few British
mitting
obstetricians would contemplate the use of prostaglandins in the circumstances we have outlined; it would be bad obstetrical practice, with a poor reward, to prove the efficacy of prostaglandin in the induction of labour in abnormal pregnancy at the expense of an increased perinatal morbidity and possibly even mortality. Academisch Ziekenhuis St. Rafael,
Leuven, Belgium. University Department of Obstetrics and Gynaecology, Southmead Hospital, Bristol. Department of Histopathology, St. George’s Hospital Medical School, London.
I. BROSENS.
H. G. DIXON.
W. B. ROBERTSON.
1. 2.
Lancet, 1973, ii, 829. Barden, T. P. in Prostaglandins: Clinical Application in Human Reproduction (edited by E. M. Southern) ; p. 193. New York,
3.
5.
Robertson, W. B., Brosens, I., Dixon, H. G. J. Path. Bact. 1967, 93, 581. Brosens, I., Robertson, W. B., Dixon, H. G. Obstet. Gynec. A. 1972, p. 177. Moghissi, K. S., Murray, C. P. Obstet. Gynec. Surv. 1970, 25,
6.
Karim, S. M.
effects in some circumstances, by preventing formation of active forms of exogenous or endogenous teratogens, but there appears no rationale or acceptable evidence for the claim that it reverses already existing birth defects when given postnatally.2 Our own study could not evaluate anti-teratogenicity, because of the low frequency of spontaneous defects in the strain used. But for this additional reason we urge further investigation. Happily, the mother mentioned above gave birth to a normal 8 lb. boy who remains in good health at age 1 year. Birth Defects Institute, New York State Department of Health, Albany, New York 12208, and Department of Pediatrics and Institute of Experimental
Toxicology, Albany Medical College Union University.
of
ERNEST B. HOOK KRISTINE M. HEALY ALLEN M. NILES RICHARD G. SKALKO.
1. Davis, A. Let’s Eat Right to Keep Fit; p. 151. New York, 1970. 2. ibid. p. 159. 3. Skalko, R. G., Packard, D. S., Jr. Expericntia, 1973, 29, 198. 4. Skalko, R. G., Packard, D. S., Jr., Schwendimann, R. N., Raggio, J. F. Teratology, 1971, 4, 87. 5. Ekalko, R. G., Gold, M. P. Teratology (in the press).
1973.
4.
281. M. Brit. J. Pharmac.
1967, 29,
230.
VITAMIN E: TERATOGEN OR ANTI-TERATOGEN?
SIR,-A former technician ingested 400 i.u. of vitadaily through her pregnancy, in the hope of preventing anaemia in her infant. The source she cited!
min E
makes many claims for vitamin E but mentions no studies of teratogenicity, nor could we find any in the scientific literature. Therefore we investigated the possible teratogenic effects of vitamin E in mice (see table). The results are consistent with, but do not substantiate, a small teratogenic effect in this strain at the dose used. The observaion of 1/91 affected fetuses excludes with 95% confidence a background rate of zero. NN7e hope other investigators will follow this lead, for it seems unwise to assume that the effects of vitamin E in pregnancy are entirely beneficial. Vitamin E, as an antioxidant, could conceivably have "anti-teratogenic"
DIFFERENTIAL N.B.T. TEST
with the negative nitroblue-tetraSIR,-In zolium-test (N.B.T.) results found in viral diseases by Park et al.,1 positive results in virus infections have been reported by several authors.2-5 We think that the type of circulating leucocyte involved in the interaction with the infectious agent should be taken into account in interpreting the results. We have done the N.B.T. test (according to the methods of Park et all and Matula and Paterson,6 with slight modifications) on granulocytes and monocytes in a number of infectious diseases. We obtained negative results (< 8% positive cells) in both granulocytes and monocytes in 20 healthy controls (see table). Patients with bacterial infections all had a positive (>8% positive cells) result in both neutrophils and monocytes. However, the frequency of positive cells per patient was in general higher in monocytes than in neutrophils. In the only patient with toxoplasmosis, the test was negative in granulocytes but positive in monocytes. Of the patients with Candida albicans septicaemia, one was negative for neutrophils and positive only for monocytes. In viral diseases the monocytes were in general positive even when the neutrophils were negative. The monocytes were negative in only two patients with varicella, contrast
VITAMIN E AND EMBRYOTOXIC PARAMETERS IN ICR
MICE*
D-a-tocopherol
acetate (vitamin E, Nutritional Biochemicals) was administered by stomach tube. Days 7-11 include the entire period of major organogeneSiS.4 Virgin ICR mice were used, whose mating and isolation have been described elsewhere.3 Their diet was Mouse Breeder Chow (Wayne). Time zero of the pregnancy was the first morning a vaginal plug was discovered. Mice were killed on day 17. Viable fetuses were examined for external malformations and then fixed in Bouin’s fluid, after which the fetal heads were dissected and examined for evidence of cleft palate.
t Including resorbed fetuses. {The largest volume administrable by stomach tube without inducing significant maternal mortality. The dose, 591 LV. of vitamin E, (1478 i.u. per ml.) for a 30 g. mouse was 19.7 i.u. per g. or 6.8 X106 i.u. per sq. m., equivalent to a dose for a 60 kg. (1.66 sq. m.) woman of 1.18 X106 i.u. by weight or 1.13 X107 by surface area. One malformed offspring with exencephaly, open eye, and micrognathia-a syndrome noted before in this strain in offspring of mice treated with known teratogens.3-5 In this laboratory it has never been observed in fetuses of a "control" mother in any experiment. The probability of the observed rate in this single experiment by Fisher’s exact test (two-tailed) is about 0.80. (The rate of all malformed in previous control series has been about l7c,, almost all with cleft palate.5)
The figure shows representative segments of polygraph tracings obtained in the women and the hamsters. The
SIR,-We describe here a system for phonographic study of breath sounds in rodents and in man which
last two segments at the bottom represent observations made in an experiment where 10 hamsters were recorded and then exposed to 8 puffs of a reference cigarette before recording the last segment in the chart. The statistical significance of the results supports the clinical impression that this simple method may be sensitive enough to detect early (acute) effects of air pollutants in human subjects. The method is also a helpful adjunct for the evaluation of experimental animals during inhalation studies. The apparatus produces permanent records of acute and chronic respiratory changes and could readily be adapted for telemetry and/or
appears to refine the performance of auscultation. This method produces permanent records for visual or computer analysis and detects, for example, early as well as chronic effects of cigarette smoking. A Grass Instrument Co. multichannel recorder model 7 was used, to which were connected E.C.G. leads (right arm/left leg), output leads of a thermocouple placed in the nares or mouth to mark inhalation and exhalation, and leads to record microphone signals taken from the chest wall. The microphone signals were also filtered and integrated to eliminate chest sounds unrelated to respiration. 205 Syrian hamsters of the BIO 87.20 and BIO 15.16 strains were subjected for up to 80 weeks to cigarette smoke from 1R1 Kentucky reference cigarettes for 8 minutes, twice a day, 5 days a week. 62 non-smoking animals were studied as controls. Variations from normal breath sounds of control hamsters were detected in most of the smoke-exposed animals by direct auscultation, and there was excellent correlation between clinical impression based on conventional auscultation and phonographic anomalies. Histopathology of the lungs was studied after pulmonary inflation and fixation under controlled pressure, and there was excellent correlation between anomalies observed microscopically and those detected by phono-
graphy. of about 25 were studied by taping the a spot in the midscapular line about 1 cm. below the shoulderblade. 1 was a chronic asthmatic, 1 a healthy non-smoker, and 1 a light-to-moderate smoker who abstained from smoking for a week before study. A control phonogram was taken of the abstaining smoker, which was identical with that of the normal subject. Immediately after inhalation of 8 puffs at 1-minute intervals from 1R1 Kentucky reference cigarettes, the wave-forms of the phonogram changed to resemble those seen in the asthmatic subject. By direct auscultation only questionable changes could be heard. 3
women
microphone
on
Phonographic recordings
of smoking and and hamsters.
non-smoking
women
personal monitoring. Bio-Research Institute, Inc., Cambridge, Massachusetts 02141, U.S.A.
C. W. LAIRD F. HOMBURGER.
Lemuel Shattuck Hospital,
Jamaica Plain, Massachusetts 02130, U.S.A.
S. ISHIKAWA.
PROSTAGLANDINS AND INDUCTION OF LABOUR
SiR,—The current preoccupation with and popularity of prostaglandin therapy in obstetrics1 is understandable since the pharmacological actions of these fatty acids make them potentially valuable therapeutic agents in a variety of conditions. We wish, however, to introduce a note of caution before these drugs are used in circumstances where they may be harmful rather than helpful. There is evidence2 that prostaglandins are more reliable and successful than oxytocin in the induction of labour before term, and in your leading article it is suggested that they may be used in the treatment of patients with, amongst other conditions, severe pre-eclampsia or cardiac disease because of the relative insensitivity of the uterus to oxytocin short of term. It would, therefore, seem
logical preferentially to use prostaglandins in those complications of pregnancy such as essential and renal hypertension, pre-eclampsia, growth-retarded fetuses, diabetes, and rhesus incompatability where induction of labour prior to term may be indicated. We think this could be false logic for the following reasons. First, there is now very good evidencë that in the hypertensive states of pregnancy pathological lesions develop in the uteroplacental arteries that almost certainly interfere with utero-placental blood-flow ; it may well be that defective maternal blood-supply to the feto-placental unit will prove to he a factor in other forms of p!acental insufficiency. Second, in pre-eclampsia there is an inadequate response of the utero-placental arteries to placentation4 resulting in their retaining more musculoelastic tissue, and hence probably being more reactive to vasomotor influences, than the corresponding placental bed arteries of normal pregnancy. Third, prostaglandm F2a has been shown to have a vasoconstrictive effect on placental veins5 and on the umbilical arteries,6 and it is thought to induce labour by causing contraction of the myometrial smooth muscle, although no studies have !cm made upon its effect on the smooth muscle of ute;’;;B blood-vessels. Consideration of these observations leads us to suspect that the exhibition of prostaglandins for the premature induction of labour in pregnancies complicated by hypertensive states, and possibly in other c(-i,ditions associated with intra-uterine hypoxia. might result in aggravation of fetal distress. The absence c: evidence of ill-effect to the fetus in prostaglandin-induced labour in normal pregnancy! is no guarantee of safet) with similar therapy in abnormal pregnancy. Before s’.ib-
809 women with abnormal pregnancies to clinical trials of induction by prostaglandins it would be wise to undertake experiments on the effect of prostaglandins on the pregnant uterus in the laboratory animal and particularly in animals where the uterus has been made ischaemic. It should not be difficult to make in-vitro studies of biopsy specimens of the human pregnant uterus, taken at the time of hysterotomy or caesarcan section, to investigate the action, if any, of prostaglandins on the myometrial blood-vessels. We think that few British
mitting
obstetricians would contemplate the use of prostaglandins in the circumstances we have outlined; it would be bad obstetrical practice, with a poor reward, to prove the efficacy of prostaglandin in the induction of labour in abnormal pregnancy at the expense of an increased perinatal morbidity and possibly even mortality. Academisch Ziekenhuis St. Rafael,
Leuven, Belgium. University Department of Obstetrics and Gynaecology, Southmead Hospital, Bristol. Department of Histopathology, St. George’s Hospital Medical School, London.
I. BROSENS.
H. G. DIXON.
W. B. ROBERTSON.
1. 2.
Lancet, 1973, ii, 829. Barden, T. P. in Prostaglandins: Clinical Application in Human Reproduction (edited by E. M. Southern) ; p. 193. New York,
3.
5.
Robertson, W. B., Brosens, I., Dixon, H. G. J. Path. Bact. 1967, 93, 581. Brosens, I., Robertson, W. B., Dixon, H. G. Obstet. Gynec. A. 1972, p. 177. Moghissi, K. S., Murray, C. P. Obstet. Gynec. Surv. 1970, 25,
6.
Karim, S. M.
effects in some circumstances, by preventing formation of active forms of exogenous or endogenous teratogens, but there appears no rationale or acceptable evidence for the claim that it reverses already existing birth defects when given postnatally.2 Our own study could not evaluate anti-teratogenicity, because of the low frequency of spontaneous defects in the strain used. But for this additional reason we urge further investigation. Happily, the mother mentioned above gave birth to a normal 8 lb. boy who remains in good health at age 1 year. Birth Defects Institute, New York State Department of Health, Albany, New York 12208, and Department of Pediatrics and Institute of Experimental
Toxicology, Albany Medical College Union University.
of
ERNEST B. HOOK KRISTINE M. HEALY ALLEN M. NILES RICHARD G. SKALKO.
1. Davis, A. Let’s Eat Right to Keep Fit; p. 151. New York, 1970. 2. ibid. p. 159. 3. Skalko, R. G., Packard, D. S., Jr. Expericntia, 1973, 29, 198. 4. Skalko, R. G., Packard, D. S., Jr., Schwendimann, R. N., Raggio, J. F. Teratology, 1971, 4, 87. 5. Ekalko, R. G., Gold, M. P. Teratology (in the press).
1973.
4.
281. M. Brit. J. Pharmac.
1967, 29,
230.
VITAMIN E: TERATOGEN OR ANTI-TERATOGEN?
SIR,-A former technician ingested 400 i.u. of vitadaily through her pregnancy, in the hope of preventing anaemia in her infant. The source she cited!
min E
makes many claims for vitamin E but mentions no studies of teratogenicity, nor could we find any in the scientific literature. Therefore we investigated the possible teratogenic effects of vitamin E in mice (see table). The results are consistent with, but do not substantiate, a small teratogenic effect in this strain at the dose used. The observaion of 1/91 affected fetuses excludes with 95% confidence a background rate of zero. NN7e hope other investigators will follow this lead, for it seems unwise to assume that the effects of vitamin E in pregnancy are entirely beneficial. Vitamin E, as an antioxidant, could conceivably have "anti-teratogenic"
DIFFERENTIAL N.B.T. TEST
with the negative nitroblue-tetraSIR,-In zolium-test (N.B.T.) results found in viral diseases by Park et al.,1 positive results in virus infections have been reported by several authors.2-5 We think that the type of circulating leucocyte involved in the interaction with the infectious agent should be taken into account in interpreting the results. We have done the N.B.T. test (according to the methods of Park et all and Matula and Paterson,6 with slight modifications) on granulocytes and monocytes in a number of infectious diseases. We obtained negative results (< 8% positive cells) in both granulocytes and monocytes in 20 healthy controls (see table). Patients with bacterial infections all had a positive (>8% positive cells) result in both neutrophils and monocytes. However, the frequency of positive cells per patient was in general higher in monocytes than in neutrophils. In the only patient with toxoplasmosis, the test was negative in granulocytes but positive in monocytes. Of the patients with Candida albicans septicaemia, one was negative for neutrophils and positive only for monocytes. In viral diseases the monocytes were in general positive even when the neutrophils were negative. The monocytes were negative in only two patients with varicella, contrast
VITAMIN E AND EMBRYOTOXIC PARAMETERS IN ICR
MICE*
D-a-tocopherol
acetate (vitamin E, Nutritional Biochemicals) was administered by stomach tube. Days 7-11 include the entire period of major organogeneSiS.4 Virgin ICR mice were used, whose mating and isolation have been described elsewhere.3 Their diet was Mouse Breeder Chow (Wayne). Time zero of the pregnancy was the first morning a vaginal plug was discovered. Mice were killed on day 17. Viable fetuses were examined for external malformations and then fixed in Bouin’s fluid, after which the fetal heads were dissected and examined for evidence of cleft palate.
t Including resorbed fetuses. {The largest volume administrable by stomach tube without inducing significant maternal mortality. The dose, 591 LV. of vitamin E, (1478 i.u. per ml.) for a 30 g. mouse was 19.7 i.u. per g. or 6.8 X106 i.u. per sq. m., equivalent to a dose for a 60 kg. (1.66 sq. m.) woman of 1.18 X106 i.u. by weight or 1.13 X107 by surface area. One malformed offspring with exencephaly, open eye, and micrognathia-a syndrome noted before in this strain in offspring of mice treated with known teratogens.3-5 In this laboratory it has never been observed in fetuses of a "control" mother in any experiment. The probability of the observed rate in this single experiment by Fisher’s exact test (two-tailed) is about 0.80. (The rate of all malformed in previous control series has been about l7c,, almost all with cleft palate.5)